This invention relates to N-hydroxy-N-[3-(2-substituted phenyl)prop-2-enyl]ureas and thioureas, compositions containing those compounds and methods of their use.
The enzyme 5-lipoxygenase (5-LO) catalyzes the first step of a biochemical synthesis pathway by which arachidonic acid is converted into leukotrienes. Numerous and extremely potent biological activities have been associated with leukotrienes. Leukotrienes have been implicated as important mediators in a variety of disease states such as asthma, ischemia, arthritis, psoriasis, allergy, adult respiratory distress syndrome (ARDS) and inflammatory bowel disease (IBD).
Considerable efforts have been directed toward the control of leukotrienes by means of leukotriene antagonists or by control of leukotriene biosynthesis. Generally, research efforts directed toward the control of leukotriene biosynthesis have been directed toward the discovery of inhibitors of the 5-LO pathway and, in particular, 5-LO specific inhibitors.
In U.K. Patent Application GB 2,196,629 certain ring substituted-N-hydroxy-N-substituted benzamide and cinnamamide compounds are disclosed as antileukotriene agents. The ring substituent may be a group having the Formula (Ra) (Rb) C.dbd.CH-- where (Ra) (Rb) C.dbd. is an unsaturated aliphatic hydrocarbylene group containing 3 to 19 carbon atoms; a group having the Formula R.sub.3 -C.tbd.C-- where R.sub.3 is a hydrogen atom or a saturated or unsaturated aliphatic hydrocarbyl group containing 1 to 18 carbon atoms; or a group having the Formula R.sub.4 -S-- where R.sub.4 is an aliphatic hydrocarbyl group containing 1 to 20 carbon atoms. The N-substituent may be a C.sub.1 -C.sub.6 alkyl group, a C.sub.3 -C.sub.7 cycloalkyl group or a substituted or unsubstituted aryl group.
In European Patent Application 0 196 184 certain aryl compounds are disclosed which include, among many others, certain cinnamohydroxamic acid analogs. Also included are certain N-aryl-N-hydroxy ureas in Examples 81-91.
In European Patent Application 0 292 699 certain urea based lipoxygenase inhibiting compounds are disclosed. These ureas include certain N-hydroxy-N-((phenyl or naphthyl or thienyl)alkyl)ureas.
In WO 90/12008 certain unsubstituted and substituted phenyl, naphthyl and thienyl N-hydroxy ureas are disclosed as inhibitors of 5- and 12-lipoxygenase. The preparation and biological activity for a number of such derivatives is disclosed.
The present invention is directed to the discovery that N-hydroxy-N-[3-(2-substituted phenyl)prop-2-enyl]ureas and thioureas, where said 2-position substituent is a hydrocarbylthio group or hydrocarbyloxy group and the hydrocarbyl radical has one or more unsaturated linkages, are potent 5-LO inhibitors. The compounds of the present invention, as defined below, are surprisingly advantageous inhibitors of 5-LO and have useful medical prophylactic and therapeutic properties. The compounds of the present invention and their pharmaceutically acceptable salts possess particularly high potency.
Accordingly, it is a primary object of the present invention to provide novel N-hydroxy-N-[3-(2-substituted phenyl)prop-2-enyl]ureas and thioureas which are potent selective 5-LO inhibitors useful in the treatment of asthma and allergic diseases, inflammatory bowel disease, ischemia, psoriasis, shock, adult respiratory distress syndrome (ARDS), and arthritis.
A further object of the present invention is to provide therapeutic compositions for treating said diseases and disorders.
Still another object is to provide methods for treating said diseases and disorders.
Other objects, features and advantages will become apparent to those skilled in the art from the following description and claims.